Carbanilide compounds

ABSTRACT

Carbanilide compounds which exhibit tuberculostatic, trypanocidal, antibabesial, antileukaemic and herbicidal properties, and which have the following formula: therapeutic 6(3-azidomethyl-2-phenylisocrotonamido)penicillanate is prepared WHEREIN A stands for m- or p-phenylene, R1-substituted m- or pphenylene, m- or p-phenyleneamino, m- or p-phenylenediamino R1substituted m- or p-phenylenediamino, p-styrylene, pphenylenedivinylene, vinylenedi-p-phenylene, or m- or ppyridylene, R1 denoting halogen, amino, nitro, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyl amino, or lower mono- or dialkylaminocarbonyl; and R are the same or different residues of one of the formulas:   R2 denoting hydrogen, alkyl having from one to five carbon atoms, or alkoxyalkyl having from one to five carbon atoms, and R3 being the same or different members of the group consisting of hydrogen, methyl, and ethyl; and (b) the therapeutically acceptable acid addition salts of (a).

United States Patent [72] Inventors Rudoli Fischer Kehrsatz, near Berne;Rudoli l-lirt, Muri, near Berne, both of Switzerland [21] Appl. No.677,031 [22] Filed Oct. 23, 1967 [45] Patented Nov. 23, 1971 [73]Assignee Dr. A. Wander, S. A.

Berne, Switzerland [32] Priority Oct. 14, 1960 [3 3] Switzerland [31]11,547/60 Mar. 9, 1962, 2880/62 Continuation-impart of application Ser.No. 263,395, Mar. 7, 1963, now abandoned which is a continuation-impartof application Ser. No. 144,294, Oct. 11, 1961, now abandoned. Thisapplication Oct. 23, 1967, Ser. No. 677,031

[54] CARBANILIDE COMPOUNDS 17 Claims, No Drawings [52] U.S. C1260/309.6, 260/157, 260/240 D, 260/240 E, 260/256.4 H, 260/294.9,260/295 PA, 260/295 E, 260/295 K, 260/465 D, 260/552 R, 260/553 A,260/553 C, 260/558 A, 260/558 S, 260/559 A, 424/273 [51] Int. Cl C07d49/34 [50] Field of 260/559 A, 559 S, 240 CA, 240 D, 256.4, 309.6. 558A, 553 A, 553 C, 295 U, 295 AM [56] References Cited UNITED STATESPATENTS 1,210,751 1/1917 Anderwert eta] 260/553 2,438,200 3/1948 Behr etal. 260/561 2,508,860 5/ l 950 Grimmel et a1. 260/518 2,832,739 4/1958Swakon 2601553 FOREIGN PATENTS 334,316 1/1959 Switzerland 260/347.3

OTHER REFERENCES Adams et al. Jour. Amer. Chem. Soc. Vol. 60, Pages1489- 1491 (1938). QDLAS Kaufler et a1. V01. 40, Pages 3261- 3262(1907). QDl.D4

Primary Examiner-Natalie Trousoe An0rneyHibben, Noyes and BicknellABSTRACT: Carbanilide compounds which exhibit tuberculostatic,trypanocidal, antibabesial, antileukaemic and herbicidal properties, andwhich have the following formula:

wherein A stands for mor p-phenylene, R -substituted m or p-phenylene,mor p-phenyleneamino, mor p-phenylenediamino R substituted morp-phenylenediamino, p-

styrylene, p-phenylenedivinylene, vinylenedi-pphenylene, or

mor p-pyridylene, R denoting halogen, amino, nitro, hydroxy, loweralkyl, lower alkoxy, lower alkylthio. lower alkanoyl amino, or lowermonoor dialkylaminocarbonyl; and R p are the same or different residuesof one of the formulae:

This is a continuation-in-part application of our 'copending Pat.applications Ser. No. 144,294, filed on Oct. 1 l, 1961, and Ser. No.263,395, filed on Mar. 7, 1963, the latter being in turn acontinuation-in-part application of the former patent application bothapplications now abandoned.

The invention relates generally to a class of new therapeutically usefulsubstances. More specifically the invention relates to the class ofchemical compounds consisting of (a) basic compounds of the formula:

and (b) therapeutically acceptable acid addition salts thereof. informula I, A has the meaning of a member of the following class ofdivalent residues: mand p-phenylene, R -substituted mand p-phenylene,mand p-phenyleneamino, mand p-phenylenediamino, R,-substituted mandp-phenylenediamino, p-styrylene, p-phenylenedivinylene,vinylenedip-phenylene, and mand p-pyridylene, R, denoting a substituentof the group consisting of halogen, amino, nitro, hydroxy, lower alkyl,lower alkoxy, lower ,alkylthio, lower alkanoylamino, and lower monoanddialkylamino-carbonyl.

The symbols R in formula I denote the same or different members of theclass consisting of basic residues having one of the following formulas:

wherein R is a member of the group consisting of hydrogen, straight orbranched alkyl having from one to five carbon atoms, and alkoxyalkylhaving from one to five carbon atoms totally; and the symbols R denotethe same or different members of the group consisting of hydrogen,methyl, and ethyl. It should be noted that R, and R in the above amidineformulas are interchangeable without alteration of the identity of thecompound.

in the foregoing formula I and hereinafter the symbol is used torepresent attachment of the substituent group at either the metaorparaposition of the benzene ring.

Subgeneric groups of compounds within the generic class of chemicalcompounds defined by formula I are as follows:

A chemical compound of the class consisting of (a) basic compounds ofthe formula selected from the group consisting of:

and

wherein R, denotes a substituent of the group consisting of halogen,amino, nitro, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, loweralkanoylamino, and lower monoand dialkylamino-carbonyl; and wherein Rare the same and are selected from the class consisting of basicresidues of the formulas:

N-R: -NH

NH-Ih and R Nil-C O-NH- wherein R are the same and are selected from theclass consisting of basic residues of the formulas:

' ii-it, N-n, N -n, NH NIH-R; N H-Ih NR;

N --n, N NH E l R; NH

R, being a member of the group consisting of hydrogen, alkyl of from oneto five carbon atoms, and alkoxyalkyl of from one to five carbon atoms,and R, being the same or different members of the group consisting ofhydrogen, methyl, and ethyl; and (b) therapeutically acceptable acidaddition salts of (a).

A chemical compound of the class consisting of (a) basic compounds ofthe fonnula selected from the group consisting of:

' minus:

and

wherein R denotes a substituent of the group'consisting of halogen,amino, nitro, hydroxy, lower'alkyl, lower alkoxy, lower alkylthio, loweralkanoylamino, and lower monoand dialkylaminmcarbonyl; and wherein R arethe same and are selected from the class consisting of basic residuesofthe formulas:

NH-CO-NHQ 20 R being a member of the group consisting of hydrogen, alkylN NH- wherein A is a member of the class consisting of mand pphenylene,R -substituted mand p-phenylene, mand pphenyleneamino, mandp-pheny|enediamino, and R -substituted mand p-phenylenediamino, R,denoting a substituent of the group consisting of halogen, amino, nitro,hydroxy, lower alkyl, lower alkoxy, lower alkylthio, lower it]-kanoylamino, and lower monoand dialkylamino-carbonyl. and R being thesame or different members of the group consisting of hydrogen, methyl,and ethyl; and (b) therapeutically acceptable acid addition salts of(a). i

Preferred compounds within the scope of this invention are, forinstance, those of the formulas:

NH NH w NH NH- CH: C H;

\ N I I NH 4 NH- HaC and the therapeutically acceptable acid additionsalts thereof. The compounds have been found to exhibit a stronggrowthinhibiting action on one or more of the following micro-organisms:Mycobaclerium tuberculosis, Trypanosoma brucei, Trypanosoma congolense,and Babesia rodaini, and/or to prolong the survival time of animalssuffering from leukemia caused by the strain L-l2l0 as shown in theaccompanying table I.

The tubercuiostatic action of the compounds of this invention wasdetermined in vitro by measurement of the lowest molar concentration(molecular weight in mg./ml.) of the active substance capable ofinhibiting the growth of Mycobacterium tuberculosis. The resultsobtained are set forth in the second column of table I below, thenumerical values denoting the negative logarithm of the molarconcentration.

The trypanocidai and/or antibabesial actions were determined by firstinjecting intraperitoneaily a certain quantity of blood obtained from amouse sufiering from trypanosomiasis or babesiosis, respectively, to agroup of healthy mice, said quantity being sufficient to cause the deathof the untreated mice within 6 to 7 days, and then injectingsubcutaneously one or several single doses of a solution or suspensionof the substance to be tested, repeated doses being administered onsubsequent days. The doses and the test results are set forth in thethird to fifth columns of table I below, the symbols used denot- 5-,prolonged survival time or recovery of part of the treated animals(death of half the number of the test animals 10 days after that of thecontrols);

++, immunization, few parasites detectable 4 weeks after the infection;and

+++, no parasites 4 weeks after the infection, complete recovery of alltest animals.

The antiieukemic action was determined by daily administeringintravenously or intraperitoneaiiy quantities of the test substancesranging from about i to 500 mg./kg. to groups of mice in which leukemiahad been induced artificially by transfer of cancer cells of the strainL-i 2 i0. The data given in column 6 of table 1 below denote thesurvival time of the treated animals expressed as percentage of thesurvival time of the untreated controls, the latter time being taken as100 percent. The active substance was injected in the form of an aqueoussolution or suspension.

The results of the tests mentioned above are summarized in the table iwith reference to the compounds of the subsequent examples.

Besides their therapeutic utility some of the compounds such as, forinstance, the product of example 9, have also valuable herbicidalproperties.

TABLE I Trypanocldal action Anti-leukaemia: action T.brucei T.conqolemeAnti-babesiai action Tuberculo- Survival Product according to staticuse, Dose, Dose, Dose l.p., time.

Ex.Nos. action mg./kg.s.c. Efiect mg./kg.s.c. Effect mg./kg.s.c. EflectmgJkgJday percent 1s 1 a I l I I l v 4 I l l l l l u 2x5 2X5 2X5 2X50I]; 280

Cominued TABLE I Trypanocidal action 7 Anti-leukaemia action T. bruceiAntibabeslal action Dose,

T. conqoleme Tuberculo- Dose i.p., Effect mgJkgJday static Dose, Dose,ion mg.!kg.s.c. Eflect mg.lkg.s.c. Eflect mg. kg.sc..

Product according to Ex. Nos.-

time. percent TABLE I Continued Trypanoeldal action Anti-leukaemicaction T. brum T. congoleme Anti-babeslal action Tuberculo- SurvivalProduct according to static Dose, Dose, Dose, Dose i.p., time. Ex. Nos.action mgJkg. 5.0. Effect mgJkg. s.c. Effect mg kg. sc.. EfiectmgJkgJday percent with either a dibasic acid of formula lll:

HOOC-ACOOH (ill) or a reactive derivative thereof, e.g. with an acidhalide, a mixed acid anhydride, or with an ester of the acid, especiallyan activated ester. if instead of a uniform amine (ll), a mixture ofdifferent kinds of amine is used, unsymmetrical compounds with differentor differently located basic residues R are obtained.

The amine is suitably reacted with the acid or with the reactivederivative thereof by adding, for instance, the acid halide at roomtemperature to the amine or to a salt thereof in a nonaqueous solvent,preferably dimethylformamide, in the presence of an acid-binding agentsuch as pyridine. Another suitable procedure consists of stirringvigorously an aqueous solution of the amine or of a salt thereof in thepresence of an acid-binding agent, e.g. sodium acetate, soda, sodiumhydroxide, pyridine or the like, with a solution of the acid halide in awater-immiscible solvent such as benzene. For purification it is useful,for example, to convert the resultant hydrochloride into the base, toproduce therefrom the water-soluble formiate or acetate, and ifnecessary to reprecipitate the hydrochloride from the aqueous solution,by adding chlorine ions.

The compounds according to formula I with one or two urea groups areobtained either by reacting two suitable amines, each of which carryingone of the two residues to be connected through the urea group, withcarboxylic acid or with a reactive carboxylic acid derivative likephosgene, or by reacting an amine which carries one of the residues tobe connected through the urea group, with an isocyanate which carriesthe other residue.

in practice, the isocyanate method is preferred and is carried out, inso far as two urea groups turn up in mirror-symmetrical arrangement inthe molecule, either by reacting one or two amines of formula ll with adiisocyanate of formula IV:

or by reacting one or two isocyanates of the formula V:

with a diamine of fonnula Vl:

l'l NANl-l In the reactions, a uniform product is obtained when uniformmonoamines or monoisocyanates are used, while mixtures of two monoaminesor monoisocyanates yield mixtures containing compounds according toformula I with dissimilar or differently located residues R.

The reaction known per se of amines with isocyanates, for which thestarting materials can be, instead of the free amines, also their saltsor reactive derivatives, is suitably carried out in a solvent, e.g.dimethylformamide or pyridine, while warming.

Compounds according to formula I can also be obtained by converting thecyano residue or residues, respectively, of a starting compound havingone of the formula VI] or Vlll:

(VII) (VIII) into the desired residue R. This reaction may be carriedout, for instance, by treating the cyano compound first with hydrogensulfide and then with the amine or diamine required for the formation ofthe desired R residue, for instance, with ethylenediamine if R should bethe imidazolinyl residue. The treatment with hydrogen sulfide may becarried out in dimethylformamide solution in the presence of a strongbase such as pyridine or triethylamine at room temperature. Thethioamide obtained may be precipitated with water and heated without asolvent to about I l0 C. with an excess of the required amine ordiamine.

The cyano compounds (Vll) or (Vlll) can also first be treated withalcoholic hydrochloric acid and then with the required amine or diamineto yield the dibasic compound of formula I.

The compounds according to formula I can be obtained as the free basesor in the form of their addition salts with inorganic or organic acids.As therapeutically acceptable acid addition salts of the dibasiccompounds according to formula I, mention can be made of the salts ofsulfuric hydrochloric, hydrobromic, hydriodic, phosphoric, formic,acetic, propionic, butyric, tartaric, maleic, oxalic, citric, salicylic,methane sulfonic, pamoic acids and the like.

The manufacture of soluble salts is suitably carried out by suspendingthe dibasic compound in water and adding the The bases or preferablytheir acid addition salts yield stable, sterilizable solutions orsuspensions in water or other fluid carriers which are suitable forinjection. The solutions can also contain other substances, but careshould be taken that these are not precipitants. Thus, sodium chloridecannot be used for the production of isotonic solutions, if the chlorineion would cause the compound to precipitate; in such cases, glucose, forexample, is more suitable for this purpose.

For instance, an aqueous suspension comprising 10 percent (w./w.) of theproduct of example 8 is prepared. An amount of glucose sufficient toyield an isotonic solution is added and the suspension isheat-sterilized in a usual manner. Said suspension is administered to amouse sufiering from L-l2 l leukemia by intraperitoneally injectingdaily amounts comprising mg./kg. of active ingredient, thus prolongingthe survival time of the animal significantly. Other compounds can beadministered in the same way, however, using difi'erent doses, inaccordance with the data given in table 1.

EXAMPLE 1 A 6.0 g. quantity of p-imidazolino-aniline dihydrochloride ina mixture of 80 ml. of dimethylformamide and 10 ml. of absolute pyridineare mixed with 2.3 g. of terephthalic acid chloride. The condensationproduct begins immediately to precipitate from the homogeneous solution.After allowing to stand for 4 hours, the reaction mixture is dilutedwith water and concentrated sodium hydroxide solution is added in orderto bind the hydrochloric acid liberated during the reaction. Theresultant organic base with the formula is drawn off and washed withwater. There is obtained a 2.6 g. quantity of the base having a meltingpoint of 350 C.

Dissolution of the base in hot, diluted acetic acid, purification withcarbon and addition of diluted hydrochloric acid yield the hydrochloridesalt which is drawn ofi and obtained, after washing with water andacetone and drying in vacuo, in a quantity of 2.7 g. with a meltingpoint at 400 C. ln similar manner, the diforrnate of melting point 400C. and the diacetate of melting point 360 C. are obtained.

EXAMPLEZ A 16.0 g. quantity of p-imidazolino-aniline is dissolved indiluted acetic acid, 40 ml. of a 50 percent solution of sodium acetateare added, and, while stirring vigorously, a benzene solution of 10.0 g.of terephthalic acid chloride is added drop by drop at room temperature.After removing the benzene in vacuo, the base is made to separate athigh temperature by ad- EXAMP E T A 4.36 g. quantity ofp-phenylene-diisocyanate (0.03 mol) and l4.04 g. ofp-imidazolino-aniline dihydrochloride (0.06 mol) are heated in a mixtureof 70 ml. of dimethylformamide and 20 ml. of absolute pyridine. For ashort time complete dis- .solution occurs and then a crystallineprecipitate appears. The

latter is drawn off, washed with dimethylformamide and alcohol,suspended in concentrated ammonia solution and allowed to stand for 4hours. The free base is drawn off and dissolved in hot diluted aceticacid. On addition of sodium chloride solution, the dihydrochloride salthaving the fonnula separates immediately and is removed by filtration,washed 5 times with water and dried in vacuo. The yield of the said saltamounts to 12.0 g., which is equivalent to 75 percent of thetheoretical. The product melts at 325 C. undergoing decomposition.

EXAMPLE 4 A 2.0 g. quantity of p-phenylene-diisocyanate and 8.0 g. ofm-(N,N'-dimethylamidino)-aniline dihydrochloride are dissolved in amixture of 40 ml. of dimethylformamide and 10 ml. of absolute pyridineby shaking, then heated for 1 hour on a steam bath and allowed to standovernight. Then the solution is filtered and 15 percent hydrochloricacid is added to the filtrate. This produces a precipitate which isdrawn off, washed 3 times with diluted hydrochloric acid and twice withether, and dried in vacuo. There are obtained- 6.8 g. of thedihydrochloride salt of the formula N-CH:

having a melting point of 265 C. (decomposition).

cu -N C Ha-N H EXAMPLE 5 melting point C.

EXAMPLE 6 Four g. of a dinitril of the formula HECQNH-CO i NH-CO-NHQ-CENobtained by reacting m-aminobenzoyl-p'-cyananiline withpcyanophenylisocyanate, are suspended in a mixture of 50 ml. ofdimethylformamide and 10 ml. of piperidine. A moderate jet of hydrogensulfide is bubbled through the suspension for 30 minutes. Thenthereaction mixture is poured into water, filtered in order to separate theprecipitated product and the latter is washed with water, diluted aceticacid and again with water. There are obtained 5 g. of a dithioamide ofthe formula S S -NHC0 NHC0-NH- HaN NHz melting point 242 C. Thisintermediate product is mixed with 30 g. of ethylenediamine and heatedfor 2 hours on a steam bath. After cooling, it is diluted with an equalvolume of ethanol and filtered in order to separate the precipitatedsolid. For the purpose of purification, this is dissolved in dilutedacetic acid, treated on warming with charcoal, separated by filtrationfrom the charcoal, and the clear filtrate is allowed to flow into anexcess of 25 percent ammonia solution. Separate the precipitated productby filtration and wash with water. There are obtained 4.5 g. of a baseof the formula NH-C ONH Z melting point 295 C. (decomposition).

in the same way as in the preceding examples, the products indicated inthe following table ll are obtained from the corresponding startingmaterials.

TABLE ll Ex. No. Product Melting point 7 N Dihydrochlorlde 340 C.

NHC 0- CONH NE NH Dihydrochlorlde NH-COCHa &

Dlhydrochlorldc Dlhydrochlorido 340 C. N J

Dehydrochlorirlo Dlhydrochloride 350 C. l NH- Dihydrochlorlde 280 C. N..NH-

Dihydrochloride Dlhydrochloridu 15m 400 0.: difornmtv NH N H- 16.. ClDihydrochlorldn 27 EXAMPLE 99 A 12 g. quantity of the condensationproduct of pimidazolinoaniline and p-amino-benzoic acid of the formulaNCH1 NII-CH:

CHz-N with a melting point at 27s 2so c.

EXAMPLE l0l A g. quantity of 4',4"-bis-(imidazolinyl-Z-)- m the form ofthe acetate are dissolved in 100 ml. of dimethyll0 therephthalanilidedihydrochloride, suspended in 130 ml. of formamide. After adding 50 g.of sodium acetate, phosgene is absolute pyridine. is boiled with 9 g. ofphosphorus pentasul-v passed in, while stirring, until the diazoreaction is negative. phide at reflux for 4 hours. After cooling, thewhole is poured The resultant basic compound of the fonnula over icewater and allowed to stand overnight. The powdery yellow product isdrawn off, washed with hot water, and dried. l 5 There are obtained 8.5g. of monophosphate of the dithio l NH C compound of the formula CHz-NHN-CH= CH1-N x CH2-NH is precipitated by adding sodium hydroxidesolution, drawn off NwCH and washed with water. 0 s -N H l The free baseis dissolved hot in 50 percent ethanol in the NH CHz presence of thenecessary quantity of glacial acetic acid. After purification of thesolution with carbon, ethanolic hydrochloa melting P (decomposition)-ric acid is added, whereupon the dihydrochloride f h By triturating withcold 2 N sodium hydroxide solution. the base separates and is then drawnoff, washed with ethanol and free a is t d therefr m. dried in vacuo.The said salt is obtained in a quantity of 7.0 g. with a melting pointof 360 C. (decomposition). EXAMPLE A 32 g. quantity ofp-aminophenylimidazoline is dissolved 7 EXAMPLE m in 500 ml. of a l:lmixture of acetone and water, and while A 20 3- quantity ofp-aminophenylimidazoline stirring, 7.5 ml. of thiophosgen are added dropby drop at dihydrochloride, suspended in a ixt f 100 f b. roomtemperature. After stirring further for PA hours, the m pyn'dine and 00f dim gh lf rm mide i mixed resultant yellow precipitate is drawn off.The still moist with 10 g. of phenylisothiocyanate-S-carboxylic acid hlfid 35 product is dissolved in 200 ml. of hot water, filtered until andwarmed, afier the reaction has subsided, for 2 hours on a clear, and anexcess of 2 N soda solution is added while warmsteam bath. Aftercooling, the product is drawn off and wh ing. The whole is allowed tocool. and the product is drawn off still moist dissolved in 300 ml.ofhot water, filtered until clear, and washed'wirh water- There areobtained 15 s of a yellow mixed with a little 2 N hydrochloric acid,allowed to cool. and product havms the formula filtered. After drying,there are obtained 13.5 g. of a pale yel- 40 CHPN Pi I n cs yqn on NCHPNH Nil-cm l g with a melting point at l73l 75 c.

By the same processes as in the preceding examples. there CH,NH are alsoobtained the productslisted in the following table Ila.

v TABLE ill I I Ex. No. Product Melting point 103.... NDlhydrocllloridl- NH NH 104--.. Dillydroclllorldn NHC O--NH- 370 c.

W: F NH- NH 105... T t h d K 320 0. NH NH- NlI-C O-NII N N-- NH Nn10s.-. Tutrallydrochloride 290 C.

TABLE Ila-Continued 144.. 'Irlhydrochlorldc TABLE Ila-Continued Meltingpoint Product e c 0 0 d m m m m m m N N M c ma t n t 0.- a M0 a 3 me Wema ma wmc N w v mw my ww u n ww w mm M 0 ma 4 N ma mw mm mm mom N N T DD D D D T T n B M m N w ill I N I: r r N N N N N N I N N K n N N N N N nI I! .N N N N N N N N N N 1L N N N N N N m H w N N N N v w 0 H N N N N NH H H o H N N u H N c M N N m w N N Y N w c w m w 0 m w a N AU N N N N ON Q m o H m O in m J .0 m m w N am N H o m m 0 0 N N ,H C 0 0 O N N N eV0 o C C H N N H c N m H N Q O a AH W N n o m n v Q o N N N N N N N N N NN. C 0 II N N N N N N N N N N N N N N N m N m N m N m N m N m N m N m Nm N m N m m m m IL |1| N N N N N N N N N

2. A therapeutically acceptable acid addition salt of a compound of theformula:
 3. The compound of the formula:
 4. A therapeutically acceptableacid addition salt of a compound of the formula:
 5. The compound of theformula:
 6. A therapeutically acceptable acid addition salt of acompound of the formula:
 7. The compound of the formula:
 8. Atherapeutically acceptable acid addition salt of a compound of theformula:
 9. The compound of the formula:
 10. A therapeuticallyacceptable acid addition salt of a compound of the formula:
 11. Thecompound of the formula:
 12. A therapeutically acceptable acid additionsalt of a compound of the formula:
 13. The compound of the formula: 14.A therapeutically acceptable acid addition salt of a compound of theformula:
 15. The compound of the formula:
 16. A therapeuticallyacceptable acid addition salt of a compound of the formula:
 17. Achemical compound of the class consisting of (a) basic compounds of theformula selected from the group consisting of: